Skip to main content
Log in

Modeling the acid–base properties of glutathione in different ionic media, with particular reference to natural waters and biological fluids

Amino Acids Aims and scope Submit manuscript

Abstract

The acid–base properties of γ-l-glutamyl-l-cysteinyl-glycine (glutathione, GSH) were determined by potentiometry (ISE-H+, glass electrode) in pure NaI(aq) and in NaCl(aq)/MgCl2(aq), and NaCl(aq)/CaCl2(aq) mixtures, at T = 298.15 K and different ionic strengths (up to I c  ~ 5.0 mol L−1). In addition, the activity coefficients of glutathione were also determined by the distribution method at the same temperature in various ionic media (LiCl(aq), NaCl(aq), KCl(aq), CsCl(aq), MgCl2(aq), CaCl2(aq), NaI(aq)). The results obtained were also used to calculate the Specific ion Interaction Theory (SIT) and Pitzer coefficients for the dependence on medium and ionic strength of glutathione species, as well as the formation constants of weak Mg j H i (GSH)(i+2j−3) and Ca j H i (GSH)(i+2j−3) complexes. Direct calorimetric titrations were also carried out in pure NaCl(aq) and in NaCl(aq)/CaCl2(aq) mixtures at different ionic strengths (0.25 ≤ I c /mol L−1 ≤ 5.0) in order to determine the enthalpy changes for the protonation and complex formation equilibria in these media at T = 298.15 K. Results obtained are useful for the definition of glutathione speciation in any aqueous media containing the main cations of natural waters and biological fluids, such as Na+, K+, Mg2+, and Ca2+. Finally, this kind of systematic studies, where a series of ionic media (e.g., all alkali metal chlorides) is taken into account in the determination of various thermodynamic parameters, is useful for the definition of some trends in the thermodynamic behavior of glutathione in aqueous solution.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

c x :

Analytical concentration, in the molar scale, of the component “x

m x :

Analytical concentration, in the molal scale, of the component “x

I :

Ionic strength

K H i :

ith protonation constant

K H0 i :

ith protonation constant at infinite dilution

γ x :

Activity coefficient of species “x” in the molal scale

y x :

Activity coefficient of species “x” in the molar scale

K D :

2-Methyl-1-propanol/aqueous salt solution distribution ratio

K 0D :

2-Methyl-1-propanol/pure water distribution ratio

k :

Setschenow coefficient

References

  • Bergen RL, Long FA (1956) The salting in of substituted benzenes by large ion salts. J Phys Chem 60(8):1131–1135. doi:10.1021/j150542a024

    Article  CAS  Google Scholar 

  • Biederman G (1975) Ionic media. In: Dahlem workshop on the nature of seawater. Dahlem Konferenzen, Berlin, pp 339–362

  • Biederman G (1986) Introduction to the specific interaction theory with emphasis on chemical equilibria. In: Jenne EA, Rizzarelli E, Romano V, Sammartano S (eds) Metal complexes in solution. Piccin, Padua, pp 303–314

    Google Scholar 

  • Braibanti A, Ostacoli G, Paoletti P, Pettit LD, Sammartano S (1987) Recommended procedure for testing the potentiometric apparatus and technique for the pH-metric measurement of metal-complex equilibrium constants. Pure Appl Chem 59:1721–1728

    Article  CAS  Google Scholar 

  • Bretti C, Foti C, Porcino N, Sammartano S (2006) SIT parameters for 1:1 electrolytes and correlation with Pitzer coefficients. J Solution Chem 35(10):1401–1415

    Article  CAS  Google Scholar 

  • Bretti C, Giacalone A, Gianguzza A, Milea D, Sammartano S (2007) Modeling S-carboxymethyl-l-cysteine protonation and activity coefficients in sodium and tetramethylammonium chloride aqueous solutions by SIT and Pitzer equations. Fluid Phase Equilibria 252:119–129

    Article  CAS  Google Scholar 

  • Bretti C, Cigala RM, Crea F, Foti C, Sammartano S (2008) Solubility and activity coefficients of acidic and basic nonelectrolytes in aqueous salt solutions. 3. Solubility and activity coefficients of adipic and pimelic acids in NaCl(aq), (CH3)4NCl(aq) and (C2H5)4NI(aq) at different ionci strengths and at t = 25°C. Fluid Phase Equilibria 263:43–54

    Article  CAS  Google Scholar 

  • Buffle J (1988) Complexation reactions in aquatic systems: an analytical approach. Ellis Horwood, Chichester

    Google Scholar 

  • Capone S, Casale A, Currò A, De Robertis A, De Stefano C, Sammartano S, Scarcella R (1986) The effect of background on the protonation of pyridine in aqueous LiCl, NaCl, KCl, RbCl, CsCl, CaCl2, MgCl2, (CH3)4NCl and (C2H5)4NI(aq) solutions at different temperatures and ionic strengths. Ann Chim (Rome) 76:441–472

    CAS  Google Scholar 

  • Cigala RM, Crea F, Lando G, Milea D, Sammartano S (2010) Solubility and acid–base properties of concentrated phytate in self-medium and in NaCl(aq) at T = 298.15 K. J Chem Thermodyn 42:1393–1399

    Article  CAS  Google Scholar 

  • Corrie AM, Williams DR (1976) Thermodynamic considerations in co-ordination. Part XXIV. Gibbs free-energy changes, enthalpies, and entropies of formation of complexes of glycinate, glycylglycinate, glycylglycylglycinate, cysteinate, and glutathionate with hydrogen and lead(II) ions and suggested aqueous structures. J Chem Soc Dalton Trans 12:1068–1072

  • Crea P, De Robertis A, De Stefano C, Milea D, Sammartano S (2007) Modelling the dependence on medium and ionic strength of glutathione acid-base behavior in LiClaq, NaClaq, KClaq, CaClaq, (CH3)4NClaq and (C2H5)4NIaq. J Chem Eng Data (52):1028–1036. doi:10.1021/je6005899

  • Crea F, Crea P, De Stefano C, Milea D, Sammartano S (2008) Speciation of phytate ion in aqueous solution. Protonation in CsClaq at different ionic strengths and mixing effects in LiClaq + CsClaq. J Mol Liquids 138:76–83. doi:10.1016/j.molliq.2007.08.024

  • Cucinotta V, Daniele PG, Rigano C, Sammartano S (1981) The formation of proton and alkali-metal complexes with ligands of biological interest in aqueous solution. Potentiometric and PMR investigation of Li+, Na+, K+, Rb+, Cs+ and NH4 + complexes with citrate. Inorg Chim Acta 56:L43

  • Daniele PG, Rigano C, Sammartano S (1982) Studies on sulphate complexes. Part I. Potentiometric investigation of Li+, Na+, K+, Rb+ and Cs+ complexes at 37°C and 0.03 < I < 0.5. Inorg Chim Acta 63:267

  • Daniele PG, Foti C, Gianguzza A, Prenesti E, Sammartano S (2008) Weak alkali and alkaline earth metal complexes of low molecular weight ligands in aqueous solution. Coord Chem Rev 252:1093–1107. doi:10.1016/j.ccr.2007.08.05

    Article  CAS  Google Scholar 

  • De Robertis A, De Stefano C, Rigano C, Sammartano S, Scarcella R (1985) Studies on acetate complexes. Part 1. Formation of proton, alkali-metal, and alkaline-earth-metal ion complexes at several temperatures and ionic strengths. J Chem Res:(S) 42(M):629–650

    Google Scholar 

  • De Robertis A, De Stefano C, Rigano C (1986a) Computer analysis of equilibrium data in solution. ES5CM Fortran and basic programs for computing formation enthalpies from calorimetric measurements. Thermochim Acta 138:141–146

    Article  Google Scholar 

  • De Robertis A, De Stefano C, Sammartano S, Calì R, Purrello R, Rigano C (1986b) Alkali-metal and alkaline-earth-metal ion complexes with adenosine 5′-triphosphate in aqueous solution. Thermodynamic parameters and their dependence on temperature and ionic strength. J Chem Res:(S) 164(M):1301–1347

    Google Scholar 

  • De Stefano C, Princi P, Rigano C, Sammartano S (1987) Computer analysis of equilibrium data in solution. ESAB2M: an improved version of the ESAB program. Ann Chim (Rome) 77:643–675

  • De Stefano C, Mineo P, Rigano C, Sammartano S (1993) Ionic strength dependence of formation constants. XVII. The calculation of equilibrium concentrations and formation constants. Ann Chim (Rome) 83:243–277

    Google Scholar 

  • De Stefano C, Foti C, Giuffrè O, Mineo P, Rigano C, Sammartano S (1996) Binding of tripolyphosphate by aliphatic amines: formation, stability and calculation problems. Ann Chim (Rome) 86:257–280

    Google Scholar 

  • De Stefano C, Sammartano S, Mineo P, Rigano C (1997) Computer tools for the speciation of natural fluids. In: Gianguzza A, Pelizzetti E, Sammartano S (eds) Marine chemistry—an environmental analytical chemistry approach. Kluwer Academic Publishers, Amsterdam, pp 71–83

    Google Scholar 

  • De Stefano C, Foti C, Giuffrè O, Sammartano S (2001) Dependence on ionic strength of protonation enthalpies of polycarboxylic anions in NaCl aqueous solution. J Chem Eng Data 46:1417–1424

    Article  Google Scholar 

  • De Stefano C, Milea D, Pettignano A, Sammartano S (2003) Speciation of phytate ion in aqueous solution. Alkali metal complex formation in different ionic media. Anal Bioanal Chem 376(7):1030–1040

    Article  PubMed  Google Scholar 

  • De Stefano C, Milea D, Sammartano S (2004) Speciation of phytate ion in aqueous solution. Thermodynamic parameters for protonation in NaCl. Thermochim Acta 423:63–69

    Article  Google Scholar 

  • De Stefano C, Milea D, Pettignano A, Sammartano S (2006) Modeling ATP protonation and activity coefficients in NaClaq and KClaq by SIT and Pitzer equations. Biophys Chem 121:121–130

    Article  PubMed  Google Scholar 

  • Dorcak V, Krezel A (2003) Correlation of acid-base chemistry of phytochelatin PC2 with its coordination properties towards the toxic metal ion Cd(II). Dalton Trans 11:2253–2259

  • Enyedy ÉA, Lakatos A, Horváth L, Kiss T (2008) Interactions of insulin–mimetic zinc(II) complexes with cell constituents: glutathione and ATP. J Inorg Biochem 102(7):1473–1485

    Article  PubMed  CAS  Google Scholar 

  • Ferretti L, Elviri L, Pellinghelli MA, Predieri G, Tegoni M (2007) Glutathione and N-acetylcysteinylglycine: protonation and Zn2+ complexation. J Inorg Biochem 101(10):1442–1456

    Article  PubMed  CAS  Google Scholar 

  • Flaschka HA (1959) EDTA titration. Pergamon Press, London

    Google Scholar 

  • Forman HJ, Zhang H, Rinna A (2009) Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med 30(1–2):1–12

    Article  PubMed  CAS  Google Scholar 

  • Foti C, Gianguzza A, Sammartano S (1997) A comparison of equations for fitting protonation constants of carboxylic acids in aqueous tetramethylammonium chloride at various ionic strengths. J Solution Chem 26(6):631–648

    Article  CAS  Google Scholar 

  • Foyer CH, Noctor G (2011) Ascorbate and glutathione: the heart of the redox hub. Plant Physiol 155(1):2–18

    Article  PubMed  CAS  Google Scholar 

  • Franco R, Cidlowski JA (2009) Apoptosis and glutathione: beyond an antioxidant. Cell Death Differ 16(10):1303–1314

    Article  PubMed  CAS  Google Scholar 

  • Fraternale A, Paoletti MF, Casabianca A, Nencioni L, Garaci E, Palamara AT, Magnani M (2009) GSH and analogs in antiviral therapy. Mol Aspects Med 30(1–2):99–110

    Article  PubMed  CAS  Google Scholar 

  • Gough JD, Lees WJ (2005) Effects of redox buffer properties on the folding of a disulfide-containing protein: dependence upon pH, thiol pKa, and thiol concentration. J Biotechnol 115(3):279–290

    Article  PubMed  CAS  Google Scholar 

  • Grenthe I, Puigdomenech I (1997) Modelling in aquatic chemistry. OECD, Paris

    Google Scholar 

  • Jan AT, Ali A, Haq QMR (2011) Glutathione as an antioxidant in inorganic mercury induced nephrotoxicity. J Postgrad Med 57(1):72–77

    Article  PubMed  CAS  Google Scholar 

  • Kulinsky VI, Kolesnichenko LS (2010) The nuclear glutathione and its functions. Biochem (Moscow) Suppl Ser B: Biomed Chem 4(3):224–227

  • Kuo MT, Chen HHW (2010) Role of glutathione in the regulation of cisplatin resistance in cancer chemotherapy. Metal-based drugs 2010. doi:10.1155/2010/430939

  • Leverrier P, Montigny C, Garrigos M, Champeil P (2007) Metal binding to ligands: cadmium complexes with glutathione revisited. Anal Biochem 371(2):215–228

    Article  PubMed  CAS  Google Scholar 

  • Madej E, Wardman P (2007) The oxidizing power of the glutathione thiyl radical as measured by its electrode potential at physiological pH. Arch Biochem Biophys 462(1):94–102. doi:10.1016/j.abb.2007.03.002

    Article  PubMed  CAS  Google Scholar 

  • Mah V, Jalilehvand F (2008) Mercury(II) complex formation with glutathione in alkaline aqueous solution. J Biol Inorg Chem 13(4):541–553. doi:10.1007/s00775-008-0342-2

    Article  PubMed  CAS  Google Scholar 

  • Marì M, Morales A, Colell A, Garcia-Ruiz C, Fernandez-Checa JC (2009) Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 11(11):2685–2700

    Article  PubMed  Google Scholar 

  • Markovic J, Garcia-Gimenez JL, Gimeno A, Vina J, Pallardò FV (2010) Role of glutathione in cell nucleus. Free Radic Res 44(7):721–733

    Article  PubMed  CAS  Google Scholar 

  • Martin HL, Teismann P (2009) Glutathione—a review on its role and significance in Parkinson’s disease. FASEB J 23(10):3263–3272

    Article  PubMed  CAS  Google Scholar 

  • Masella R, Mazza G (2009) Glutathione and sulfur amino acids in human health and disease. Wiley, Hoboken

    Book  Google Scholar 

  • Millero FJ (1982) Use of models to determine ionic interactions in natural waters. Thalassia Jugoslavica 18(1–4):253–291

    Google Scholar 

  • Millero FJ (2001) Physical chemistry of natural waters. In: Wiley-interscience series in geochemistry. Wiley, New York

  • Mohammadirad A, Abdollahi M (2011) A systematic review on oxidant/antioxidant imbalance in aluminium Toxicity. Int J Pharmacol 7(1):12–21

    Article  CAS  Google Scholar 

  • Noszal B, Szakacs Z (2003) Microscopic protonation equilibria of oxidized glutathione. J Phys Chem B 107:5074–5080

    Article  CAS  Google Scholar 

  • Pallardò FV, Markovic J, Garcia JL, Vina J (2009) Role of nuclear glutathione as a key regulator of cell proliferation. Mol Aspects Med 30(1–2):77–85

    Article  PubMed  Google Scholar 

  • Perricone C, De Carolis C, Perricone R (2009) Glutathione: a key player in autoimmunity. Autoimmun Rev 8(8):697–701

    Article  PubMed  CAS  Google Scholar 

  • Pitzer KS (1973) Thermodynamics of electrolytes. I. Theoretical basis and general equations. J Phys Chem 77(2):268–277

    Article  CAS  Google Scholar 

  • Pitzer KS (1991) Activity coefficients in electrolyte solutions, 2nd edn. CRC Press, Inc., Boca Raton

    Google Scholar 

  • Schubert J (1954) Complexes of alkaline earth cations including radium with amino acids and related compounds. J Am Chem Soc 76(13):3442–3444. doi:10.1021/ja01642a021

    Article  CAS  Google Scholar 

  • Schwarzenbach G (1957) Complexometric titrations. Methuen & Co., Ltd, London

    Google Scholar 

  • Setschenow JZ (1889) Uber Die Konstitution Der Salzlosungenauf Grund Ihres Verhaltens Zu Kohlensaure. Z Physik Chem 4:117–125

    Google Scholar 

  • Singh PK, Garg BS, Kumar DN, Singh BK (2001) Complexation equilibria and evaluation of thermodynamic parameters of bivalent metal complexes of glutathione. Ind J Chem Sect A Inorg Bio-inorg Phys Theor Anal Chem 40A(12):1339–1343

    CAS  Google Scholar 

  • Szalai G, Kellos T, Galiba G, Kocsy G (2009) Glutathione as an antioxidant and regulatory molecule in plants under abiotic stress conditions. J Plant Growth Regul 28(1):66–80

    Article  CAS  Google Scholar 

  • Tew KD, Townsend DM (2011) Redox platforms in cancer drug discovery and development. Curr Opin Chem Biol 15(1):156–161

    Article  PubMed  CAS  Google Scholar 

  • Touche MLD, Williams DR (1976) Thermodynamic considerations in co-ordination. Part XXV. Formation of ternary complexes containing two dissimilar metal ions and the implication for metal–metal stimulation phenomena in vivo. J Chem Soc Dalton Trans 14:1355–1359

  • Vander Jagt DL, Hansen LD, Lewis EA, Han L-PB (1972) Calorimetric determination of the micro ionization constants of glutathione. Arch Biochem Biophys 153(1):55–61

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Li K, Yang XD, Wang LL, Shen RF (2009) Complexation of Al(III) with reduced glutathione in acidic aqueous solutions. J Inorg Biochem 103(5):657–665

    Article  PubMed  CAS  Google Scholar 

  • Yadav SK (2010) Heavy metals toxicity in plants: an overview on the role of glutathione and phytochelatins in heavy metal stress tolerance of plants. S Afr J Bot 76(2):167–179

    Article  CAS  Google Scholar 

  • Yang XD, Zhang QQ, Chen RF, Shen RF (2008) Speciation of aluminum(III) complexes with oxidized glutathione in acidic aqueous solutions. Anal Sci 24(8):1005–1012. doi:10.2116/analsci.24.1005

    Article  PubMed  CAS  Google Scholar 

  • Yuan L, Kaplowitz N (2009) Glutathione in liver diseases and hepatotoxicity. Mol Aspects Med 30(1–2):29–41

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the University of Messina (PRA) for financial support.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Silvio Sammartano.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cigala, R.M., Crea, F., De Stefano, C. et al. Modeling the acid–base properties of glutathione in different ionic media, with particular reference to natural waters and biological fluids. Amino Acids 43, 629–648 (2012). https://doi.org/10.1007/s00726-011-1110-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00726-011-1110-0

Keywords

Navigation